Dr. John K. Amory is applying for this Mentored Patient-Oriented Research Career Development Award (K23). Dr. Amory's career goal is to become an independent clinician-investigator proficient in the design and conduct of research evaluating the use of existing and novel androgens in: 1) the treatment of testosterone deficiency in young men; 2) the development of hormonal contraceptives for men; and 3) in male aging. Having gained considerable experience in designing and conducting clinical research relating to the uses of androgens, he now proposes mentored research and didactic training to facilitate the development and evaluation of novel means of oral androgen delivery for men with testosterone deficiency. He proposes a comprehensive assessment of the potential utility of high-dose oral testosterone administration. In his initial study, normal men will be rendered transiently testosterone deficient, and then administered increasing doses of high-dose testosterone by mouth, something not previously tested. Careful pharmacokinetic analysis will allow Dr. Amory to determine the optimal dosages for further study. In subsequent studies of oral testosterone therapy, testosterone deficient (hypogonadal) men currently receiving testosterone therapy will be treated with either oral testosterone or currently available testosterone therapy and followed both short and long-term to assess the ability of oral testosterone to serve as androgen replacement therapy. Validated tools for the assessment of mood, energy and sexual function for the assessment of short-term androgen endpoints will be used to compare the effects of the oral testosterone to currently used testosterone therapy. Long-term androgen-responsive endpoints such as bone mineral density, body composition and prostate volume will be followed to ascertain the impact of oral androgen therapy on men with testosterone deficiency. Data from these studies will eventually guide the design of larger, more definitive trials of oral androgen replacement, which could eventually lead to the clinical use of oral testosterone in the treatment of testosterone deficiency, and potentially in the treatment of age-related conditions and in the development of a male hormonal contraceptive. William J. Bremner, M.D., Ph.D., Chairman of the Department of Medicine, and Director of the Center for Research in Human Reproduction and Center for Contraceptive Development and Alvin M. Matsumoto M.D., Director, Clinical Research Unit VA-Puget Sound and Professor of Medicine, University of Washington School of Medicine will co-mentor this award. [unreadable] [unreadable]